Prognostic impact of digitally quantified tumor-infiltrating lymphocytes in HR+/HER2- metastatic breast cancer treated with CDK4/6 inhibitors.

Abstract

1112 Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors plus endocrine therapy are the first-line treatment for hormone receptor (HR)-positive/HER2-negative metastatic breast cancer(MBC). Prognostic biomarkers are needed to guide treatment decisions. Although Tumor-infiltrating lymphocytes (TILs) have been studied in breast cancer, their prognostic value in HR+/HER2- MBC remains unclear. Therefore, we aimed to assess the prognostic value of TILs in this patient population. Methods: We retrospectively analyzed patients with HR+/HER2- MBC receiving CDK4/6 inhibitors (palbociclib, ribociclib, or abemaciclib) plus endocrine therapy at Gangnam Severance Hospital, Seoul, Republic of Korea, from 2017 to 2025. We included 180 of 326 treated patients who met prespecified criteria. TILs were assessed according to the International Immuno-Oncology Biomarker Working Group guidelines using the digital pathology software QuPath (v0.6.0). Stromal TILs were quantified in two representative regions of interest (ROIs; each approximately 1,000 µm wide) using the formula TIL (%) = [immune cell area / (annotation area – tumor cell area)] × 100, and the values were averaged across ROIs. Patients were classified into high- and low-TIL groups using the median TIL as the cutoff. Progression-free survival (PFS) and overall survival (OS) were compared using Kaplan-Meier analyses and log-rank tests. Hazard ratios (HRs) were estimated using Cox proportional hazards models. Results: Among 180 patients, the median age was 53.9 years (range, 28.0–87.5) and the median follow-up was 32.4 months (range, 4.6–104.4). Median PFS was 23.2 months (98 progression events) and median OS was 32.4 months (28 death events). Using a median TIL cutoff of 7.31%, 90 patients were classified into each group. The high-TIL group showed numerically longer PFS than the low-TIL group (median 35.2 vs. 28.1 months, 95% confidence interval [CI] 25.6–not reached[NR] vs. 22.7–42.0; log-rank p=0.15; HR 0.75, 95% CI 0.50–1.12; Cox p=0.154). For OS, the high-TIL group had significantly longer survival (median NR in both groups; log-rank p=0.028; HR 0.41, 95% CI 0.18–0.93; Cox p=0.033). In the primary breast tumor subset (n=111), similar trends were observed for PFS (median 42.2 vs 27.6 months; 95% CI 24.8–NR vs 19.3–61.4; log-rank p=0.072; HR 0.62, 95% CI 0.36–1.05; Cox p=0.075) and OS (median NR in both groups; log-rank p=0.073; HR 0.41, 95% CI 0.15–1.13; Cox p=0.083). Conclusions: Higher TIL levels may be associated with more favorable outcomes in patients with HR+/HER2- MBC treated with CDK4/6 inhibitor-based therapy. In contrast, patients with low TILs, who may derive less benefit, could be considered for alternative targeted therapies or chemotherapy. These findings suggest TILs may have prognostic value in this setting and warrant confirmation in further prospective, multicenter studies.